The goal of this project is to develop an anti-nicotine vaccine for smoking cessation. Smoking-related diseases are the leading cause of preventable death and morbidity. Although 70% of smokers desire to quit and 40% of smokers attempt to stop smoking each year, less than 10% of these attempts are successful. The Centers for Disease Control and Prevention estimates that smoking is responsible for $96 billion a year in direct health care costs and an additional $97 billion a year in lost productivity in the United States. Clearly, an urgent global need exists for more efficacious approaches to smoking cessation therapy. A promising approach is to vaccinate against nicotine, inducing nicotine specific antibodies to capture nicotine in the blood and inhibit passage to the brain, thus eliminating its addiction-reinforcing activities. Supportive data from independent phase 2 and phase 3 clinical trials indicate a correlation between high anti-nicotine antibody levels and smoking cessation. However these vaccines were not differentiated from placebo, as only a small portion of subjects achieved high enough nicotine antibody levels to aid in smoking cessation. Previous nicotine vaccine trials used the conventional vaccine strategy of linking the nicotine to a protein (a hapten-carrier approach). We postulate that a fundamentally new technology is needed to increase anti-nicotine titers. Selecta Biosciences has developed a novel approach to vaccine design to boost immune responses well beyond that of conventional technologies. Selecta's technology consists of synthetic immunomodulatory nanoparticles that home to antigen presenting cells (dendritic cells and B cells) to drive focused and highly prolific antigen-specific immune responses. The nanoparticles can be precisely engineered and comprise all of the key elements required to optimize an immune response: 1) Targeting to antigen presenting cells (APC) to enhance efficacy and reduce off target impact; 2) B-cell antigen (nicotine) presentation at high surface density to stimulate robust and rapid B-cell responses; 3) T-cell antigen (TCHP) to provide T cell help for affinity maturation of B cell responses and efficient generation of immune memory; 4) Adjuvant (Toll-like receptor agonist) for APC activation, and 5) Biocompatible polymers for the time release of active components. Selecta conducted a Phase 1 clinical trial of a first generation nicotine vaccine (SEL-068) consisting of a single particle formulation containing all three active components (TLR agonist, TCHP, and nicotine). SEL-068 was well tolerated and generated nicotine specific antibodies. In this grant we propose to test additional nicotine nanoparticle formulations to further increase the level of anti-nicotine antibodies in humans using a two particle nicotine vaccine in which the TLR agonist and TCHP will be formulated in separate nicotine-containing nanoparticles. The two particles can be mixed and dosed at various ratios and dose levels in the clinic to optimize the human anti-nicotine antibody response. The scope of the grant proposal is formulation, preclinical studies, scale-up and manufacturing and an adaptive design Phase 1 clinical trial.